Furopyridine and furopyrimidine derivatives for the treatment of hyper-proliferative disorders

ABSTRACT

This invention relates to a compound of Formula (I) wherein Y is CH or N; Ar 1  is phenyl or pyridyl each optionally substituted with 1 or 2 substituents each selected independently from (C 1 -C 3 )alkoxy halo, OH, CF 3 , CN, NO 2  and (C 1 -C 3 )alkyl, said alkyl being optionally substituted with CF 3 ; Ar 2  is phenyl or pyridyl each option-ally substituted with 1 or 2 substituents each independently selected from halo, OH, CN, NO 2 , CF 3 , (C 1 -C 6 )alkoxy, NR 1 R 1 , S(O) 2 R 2 , C(O)R 3 , and (C 1 -C 6 )alkyl optionally substituted with R 4 , and its use in treating hyper-proliferative disorders.

This patent application claims priority to U.S. Provisional Application60/395065 filed on Jul. 11, 2002.

FIELD OF THE INVENTION

This invention relates to novel furopyridine and furopyrimidinecompounds, pharmaceutical compositions containing such compounds, andthe use of those compounds or compositions for treatinghyper-proliferative disorders.

DESCRIPTION OF THE INVENTION

One embodiment of this invention is a compound of Formula I

wherein

-   -   Y is CH or N;    -   Ar¹ is phenyl or pyridyl each optionally substituted with 1 or 2        substituents each being independently selected from        (C₁-C₃)alkoxy, halo, OH, CF₃, CN, NO₂and (C₁-C₃)alkyl, said        alkyl being optionally substituted with CF₃;    -   Ar² is phenyl or pyridyl each optionally substituted with 1 or 2        substituents each being independently selected from halo, OH,        CN, NO₂, CF₃, (C₁-C₆)alkoxy, NR¹R¹, S(O)₂R², C(O)R³, and        (C₁-C₆)alkyl optionally substituted with R⁴;    -   R¹ is selected from H, S(O)₂N[(C₁-C₃)alkyl]₂,        S(O)₂NH(C₁-C₃)alkyl, C(O)(C₁-C₃)alkyl where said alkyl is        optionally substituted with NR⁵R⁵, and (C₁-C₃)alkyl where said        alkyl is optionally substituted with 1 or 2 substituents each        selected independently from OH and (C₁-C₃)alkoxy,        -   with the proviso that in any NR¹R¹ group when one R¹ is            S(O)₂N[(C₁-C₃)alkyl]₂, S(O)₂NH(C₁-C₃)alkyl or            C(O)(C₁-C₃)alkyl then the other R¹ must be other than            S(O)₂N[(C₁-C₃)alkyl]₂, S(O)₂NH(C₁-C₃)alkyl or            C(O)(C₁-C₃)alkyl;    -   R² is selected from (C₁-C₃)alkyl, pyrrolidinyl, and        NH(C₁-C₃)alkyl where said alkyl is optionally substituted with        OH;    -   R³ is selected from (C₁-C₃)alkyl, (C₁-C₃)alkoxy, morpholinyl,        pyrrolidinyl, piperidinyl, and NH(C₁-C₃)alkyl where said alkyl        is optionally substituted with OH, (C₁-C₃)alkoxy or        N[(C₁-C₃)alkyl]₂;    -   R⁴ is selected from OH, CN, CF₃, (C₁-C₃)alkoxy, C(O)NR⁵R⁵,        NR⁵R⁵, and piperidinyl; and    -   R⁵ is selected from H, (C₁-C₃)alkyl, C(O)(C₁-C₃)alkyl,        S(O)₂(C₁-C₃)alkyl and piperidinyl, with the proviso that in any        NR⁵R⁵ group when one R⁵ is C(O)(C₁-C₃)alkyl or        S(O)₂(C₁-C₃)alkyl, then the other R⁵ must be other than        C(O)(C₁-C3)alkyl or S(O)₂(C₁-C₃)alkyl; and    -   excluding        (3-amino-6-phenylfuro[2,3b]pyridin-2-yl)(phenyl)methanone,        (3-amino6-phenylfuro[2,3b]pyridin-2-yl)(4nitrophenyl)methanone,        and        (3-amino6-(4-methylphenyl)furo[2,3-b]pyridin-2-yl)(phenyl)methanone,        or a pharmaceutically acceptable salt thereof.

The terms identified above have the following meaning throughout:

The term “optionally substituted” means that the moiety so modified mayhave from none to up to at least the highest number of substituentsindicated. A substituent may replace any H atom on the moiety somodified as long as the replacement is chemically possible andchemically stable. When there are two or more substituents on anymoiety, each substituent is chosen independently of any othersubstituent and can, accordingly, be the same or different.

The terms “(C₁-C₃)alkyl” and “(C₁-C₆)alkyl” mean a linear or branchedsaturated carbon group having from 1 to about 3 or about 6 C atoms,respectively. Such groups include but are not limited to methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and thelike.

The terms “(C₁-C₃)alkoxy” and “(C₁-C₆)alkoxy” mean a linear or branchedsaturated carbon group having from 1 to about 3 or about 6 C atoms,respectively, said carbon group being attached to an O atom. The O atomis the point of attachment of the alkoxy substituent to the rest of themolecule. Such groups include but are not limited to methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, andthe like.

The term “halo” means an atom selected from Cl, Br, F.

When Ar¹ and/or Ar² is pyridyl, the pyridyl ring(s) may be attached tothe core molecule at any available C atom.

When any R group or any substituent is pyrrolidinyl, piperidinyl, ormorpholinyl, the ring may be attached to the rest of the moleculethrough any available C or N atom.

NR¹R¹ and NR⁵R⁵ in each instance means that each R¹ group or R⁵ group,respectively, is selected independently from the other so that they maybe the same or they may be different. Also, in each N[(C₁-C₃)alkyl]₂group, each of the two alkyl groups is selected independently from theother so that they may be the same or they may be different.

When (O) is in a formula, it means ═O; that is, an oxygen atom doublebonded to the C atom to which it is attached.

When a phenyl or a pyridyl ring is substituted with one or moresubstituent, the substituent(s) may be attached to the phenyl ring atany available C atom. When there is more than 1 substituent on a ring,each is selected independently from the other so that they may be thesame or different.

Representative compounds of Formula I are shown in Table 2. TABLE 1Fused furopyridines (Ia)

HPLC/ES-MS* Example [M + H]+ No. X Ar (R_(t), min) 1 CH₂

353.1 (2.87) 2 CH₂

308.2 (2.26) 3 CH₂

361.2 (3.40) 4 CH₂

362.2 (2.89) 5 CH₂

323.1 (2.85) 6 CH₂

323.2 (3.13) 7 CH₂

321.1 (3.29) 8 CH₂

311.2 (2.98) 9 O

363.1 (2.95) 10 O

323.2 (2.71) 11 O

325.1 (2.95) 12 O

325.2 (2.54) 13 O

364.2 (2.28) 14 N-Me

377.1 (1.50) 15 N-Me

376.1 (2.08)

TABLE 2 Phenyl substituted furopyridines and furopyrimidines (I)

HPLC/ES-MS Example [M + H]+ No. Ar¹ Ar² Y (R_(t), min) 16

CH 363.4 (3.56) 17

CH 401.3 (3.77) 18

N 385.0 (3.92) 19

N 346.0 (3.40) 20

N 352.0 (3.45) 21

CH 22

CH 23

CH 24

CH 25

CH 26

CH 27

CH 28

CH 29

CH 30

CH 31

CH 32

CH 33

CH 34

CH 35

CH 36

CH 37

CH 38

CH 39

CH 40

CH 41

CH 42

CH 43

N 44

N 45

N 46

N 47

N 48

N 49

N 50

N 51

N 52

N 53

N 54

N 55

N 56

N 57

N 58

N 59

N 60

N 61

N*HPLC-electrospray mass spectra (HPLC ES-MS) data listed in Tables 1 and2 were obtained using a Hewlett-Packard 1100 HPLC equipped with aquaternary pump, a variable wavelength detector set at 254 nm, a YMC proC-18 column (2 × 23 mm, 120A), and a Finnigan LCQ ion trap massspectrometer with electrospray ionization. Spectra were scanned from120-1200 amu using a variable ion time according to the number of ionsin the source. The eluants were A:2%# acetonitrile in water with 0.02% TEA and B:2% water in acetonitrilewith 0.018% TFA. Gradient elution from 10% B to 95% over 3.5 minutes ata flow rate of 1.0 mL/min was used with an initial hold of 0.5 minutesand a final hold at 95% B of 0.5 minutes. Total run time was 6.5minutes. All compound structures are consistent with the analytical datapresented.

The compound structures of Tables 1 and 2 correspond to the IUPACcompound names below. Example No. IUPAC Name* 1(3-amino-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-2-yl)-(2,5-dimethoxyphenyl)methanone 2(3-amino-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-2-yl)-(4-methyl-3-pyridinyl)methanone 3(3-amino-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-2-yl)-(2,4-dichlorophenyl)methanone 4(3-amino-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-2-yl)-[4-(trifluoromethyl)-3-pyridinyl]methanone 5(3-amino-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-2-yl)-(2-methoxyphenyl)methanone 6(3-amino-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-2-yl)(3-methoxyphenyl)methanone 7(3-amino-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-2-yl)-(2,4-dimethylphenyl)methanone 8(3-amino-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-2-yl)-(2-fluorophenyl)methanone 9(3-amino-7,8-dihydro-5H-furo[2,3-b]pyrano[3,4-e]pyridin-2-yl)(2,4-dichlorophenyl)methanone 10(3-amino-7,8-dihydro-5H-furo[2,3-b]pyrano[3,4-e]pyridin-2-yl)(2,4-dimethylphenyl)methanone 11(3-amino-7,8-dihydro-5H-furo[2,3-b]pyrano[3,4-e]pyridin-2-yl)(2-methoxyphenyl)methanone 12(3-amino-7,8-dihydro-5H-furo[2,3-b]pyrano[3,4-e]pyridin-2-yl)(3-methoxyphenyl)methanone 13(3-amino-7,8-dihydro-5H-furo[2,3-b]pyrano[3,4-e]pyridin-2-yl)[4-(trifluoromethyl)-3-pyridinyl]methanone 14(3-amino-6-methyl-5,6,7,8-tetrahydrofuro[2,3-b]-1,6-naphthyridin-2-yl)[4-(trifluoromethyl)-3-pyridinyl]methanone 15(3-amino-6-methyl-5,6,7,8-tetrahydrofuro[2,3-b]-1,6-naphthyridin-2-yl)(2,4-dichlorophenyl)methanone 16[3-amino-6-(4-fluorophenyl)furo[2,3-b]pyridin-2-yl](3-methoxyphenyl)methanone 17[3-amino-6-(4-fluorophenyl)furo[2,3-b]pyridin-2-yl](2,4-dichlorophenyl)methanone 18(5-amino-2-phenyl-furo[2,3-d]pyrimidin-6-yl)-(2,4-dichloro-phenyl)-methanone 19(5-amino-2-phenyl-furo[2,3-d]pyrimidin-6-yl)-(3-methoxy-phenyl)-methanone 20(5-amino-2-phenyl-furo[2,3-d]pyrimidin-6-yl)-(2,4-difluoro-phenyl)-methanone*The IUPAC name was obtained using the ACD/ILab Web service

The compounds of this invention may contain one or more asymmetriccenters, depending upon the location and nature of the varioussubstituents desired. Asymmetric carbon atoms may be present in the (R)or (S) configuration or (R,S) configuration. In certain instances,asymmetry may also be present due to restricted rotation about a givenbond, for example, the central bond adjoining two substituted aromaticrings of the specified compounds. Substituents on a ring may also bepresent in either cis or trans form, and a substituent on a double bondmay be present in either =Z- or =E-form. It is intended that all suchconfigurations (including enantiomers and diastereomers), are includedwithin the scope of the present invention. Preferred compounds are thosewith the absolute configuration of the compound of this invention whichproduces the more desirable biological activity. Separated, pure orpartially purified isomers or racemic mixtures of the compounds of thisinvention are also included within the scope of the present invention.The purification of said isomers and the separation of said isomericmixtures can be accomplished by standard techniques known in the art.

Pharmaceutically acceptable salts of these compounds are also within thescope of this invention. The term “pharmaceutically acceptable salt”refers to a relatively non-toxic, inorganic or organic salt of acompound of the present invention. For example, see S. M. Berge, et al.“Pharmaceutical Salts,” J. Pharm. Sci., 66: 1-19, 1977.

Representative salts of the compounds of this invention include theconventional non-toxic salts and the quaternary ammonium salts that areformed, for example, from inorganic or organic acids or bases by meanswell known in the art. For example, such acid addition salts includeacetate, adipate, alginate, ascorbate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, citrate, camphorate,camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate,dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate,maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate,nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate,3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate,tartrate, thiocyanate, tosylate, and undecanoate.

Base salts include alkali metal salts such as potassium and sodiumsalts, alkaline earth metal salts such as calcium and magnesium salts,and ammonium salts with organic bases such as dicyclohexylamine andN-methyl-D-glucamine. Additionally, basic nitrogen containing groups maybe quaternized with such agents as lower alkyl halides such as methyl,ethyl, propyl, and butyl chlorides, bromides and iodides; dialkylsulfates like dimethyl, diethyl, and dibutyl sulfate; and diamylsulfates, long chain halides such as decyl, lauryl, myristyl andstrearyl chlorides, bromides and iodides, aralkyl halides like benzyland phenethyl bromides and others.

METHOD OF MAKING THE COMPOUNDS OF THE PRESENT INVENTION

In general, the compounds of this invention may be prepared by standardtechniques known in the art, by known processes analogous thereto,and/or by processes disclosed below, using starting materials which areeither commercially available or producible according to routine,conventional chemical methods.

The particular process to be utilized in the preparation of thecompounds of this invention depends upon the specific compound desired.Such factors as the selection of Y, or the Ar groups, and the specificsubstituents possible at various locations on the molecule, each play arole in the path to be followed in the preparation of the specificcompounds of this invention. Those factors are readily recognized by oneof ordinary skill in the art.

The compounds of the present invention are prepared generally accordingto Reaction Scheme 2 and Reaction Scheme 3.

DEFINITIONS

When the following abbreviations are used herein, they have thefollowing meaning: DMF N,N-dimethylformamide DMSO dimethylsulfoxide Et₂Odiethyl ether EtOH ethanol HPLC ES-MS high performance liquidchromatography- electrospray mass spectroscopy LC/MS LiquidChromatography/Mass Spectroscopy MeOH methanol NMR Nuclear MagneticResonance Spectroscopy RT retention time (HPLC) R_(f) TLC RetentionFactor rt room temperature TFA trifluoroacetic acid TLC thin layerchromatography

The general method of Reaction Scheme 1 through intermediate (5) isdescribed in Paine, J. B. J. Heterocycl. Chem. 1987, 24, 351. By analogyto the Paine method, this method may be used for preparation of theprecursor compounds (5) in Reaction Scheme 1 below where X is CH₂, O or—N(Me), and Ar represents a substituted phenyl or substituted pyridylring.

Generally, ethanol and ether are mixed with sodium ethoxide and cooledto 0° C. A cyclic ketone (1) and ethyl formate (2) are then added andallowed to react at room temperature to form the hydroxy methyleneketone salt (3), the isolation of which may be facilitated using ether.The salt (3) is then mixed with cyanoacetamide (4) in water andpiperidine acetate and refluxed with acetic acid to yield the pyridone(5). The appropriate haloarylketone (6) and potassium carbonate areadded to the pyridone (5) in DMF, and the mixture is heated under Argonto yield the compounds la in Table 1.

A specific example of this preparation is described next.

PREPARATION OF COMPOUND EXAMPLE 1(3-amino-5,6,7,8-tetrahydrofuro[2,3-]quinolin-2-yl)(2,5-dimethoxyphenyl)methanone(Compound 1a of Reaction Scheme 1 where X is CH₂, and Ar¹ is2,5-diMeO-Ph-)

Step 1: Preparation of sodium (E)-(2-oxocyclohexylidene)methanolate:(3), X is CH₂

In a 100 mL flask was placed 5 mL of EtOH and 30 mL of Et₂O. To this wasadded NaOEt (1.78 g, 26.1 mmol, 1 equiv.) and the flask was cooled to 0°C. where cyclohexanone (1) (X is CH₂, 2.56 g, 26.1 mmol, 1 equiv) wasadded. After 10 minutes, ethyl formate (2.03 g, 27.4 mmol, 1.05 equiv)was added dropwise, the ice bath was removed, and the mixture wasallowed to stir overnight at room temperature.

The mixture was then diluted with enough Et₂O to fill the flask and thesolids were filtered. The solids were then rinsed with Et₂O (100 mL )and dried under high vacuum at 50° C. for 30 minutes to remove anyresidual Et₂O. Isolated 2.57 g (17.3 mmol, 63%) of the desired productas a white solid. ¹H-NMR (D₂O) δ 8.25(s,1H), 2.03 (q, 4H), 1.51 (m, 2H),1.42 (m, 2H).

Step 2: Synthesis of2-hydroxy-5,6,7,8-tetrahydro-3-quinolinecarbonitrile: (5) X is CH₂

In a 50 mL flask was placed the product of step 1 ((3), X is CH₂, 2.0 g,13.5 mmol, 1 equiv) and cyanoacetamide (4) (1.24 g, 14.7 mmol, 1.09equiv) in 10 mL of water and 1 mL of piperidine acetate (prepared byadding 7.2 mL of piperidine to a cold solution of 4.2 mL acetic acid in10.0 mL of water). This was refluxed for 3.5 h at which point 1.5 mL ofacetic acid was slowly added to the hot solution. This caused vigorousboiling and effervescence. The mixture was allowed to stir to roomtemperature overnight.

The precipitated solids were then filtered off and washed with water (30mL ) to provide only 422 mg (2.4 mmol, 18%) of the desired product as awhite solid. ¹H-NMR (DMSO-d₆) δ12.26 (s, 1H), 7.87 (s, 1H), 2.55 (t,2H), 2.41 (t, 2H), 1.65 (m, 4H).

Step 3: Synthesis of the title compound3-amino-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-2-yl)(2,5-dimethoxyphenyl)methanone

In a 20 mL vial was placed the product of step 2 ((5), X is CH₂, 100.0mg, 0.57 mmol, 1 equiv) and K₂CO₃ (87.3 mg, 0.63 mmol, 1.1 equiv) in 4mL of DMF. This was allowed to stir for 5 minutes at 40° C. where 156.2mg (0.60 mmol, 1.1 equiv.) 2-bromo-1-(2,5-methoxyphenyl)ethanone wasadded, the vial capped under Argon, and the reaction heated to 80° C.overnight in a sand bath.

The DMF was then removed, the residue dissolved in MeOH, filtered andfurther purified via HPLC (10-100% MeOH/H2O) to provide 34.7 mg (0.09mmol, 21%) of the desired compound as a yellow solid. ¹H-NMR (CD₃CN) δ7.90 (s, 1H), 7.06 (s, 2H), 6.98 (s, 1H), 3.79 (s, 3H), 3.75 (s, 3H),2.91 (m, 4H), 1.87 (m, 4H); LC/MS R_(t)=2.87 min.; [M+H]⁺=353.1.

Compounds of Table 1 where X is O or N-methyl can be prepared in a likemanner using tetrahydro-4H-pyran-4one or 1-methyl-4-piperidinone for therespective cyclic ketone (1) starting material.

The reference method of Paine cited above also may be used by analogyfor preparation of each of the intermediate compounds (9) of ReactionScheme 2 below that are useful for making the compounds of Formula Iwhere Y is CH.

Generally, ethanol and ether are mixed with sodium ethoxide and cooledto 0° C. Acetophenone (7) and ethyl formate (2) are then added andallowed to react at room temperature to form the hydroxymethylene ketonesalt (8), the isolation of which may be facilitated using ether. Thesalt (8) is then mixed with cyanoacetamide (4) in water and piperidineacetate and refluxed with acetic acid to yield the pyridone (9). Thehaloalkylaryl ketone (6) and potassium carbonate were added to thepyridone (9) in DMF, and the mixture was heated under Argon to yield thecompounds 1b in Table 2. Specifically, the haloalkylaryl ketones (6)2-bromo-3′-methoxyacetophenone and 2,2′,4′-trichloroacetophenone wereused to make the end products Example 16 and Example 17 in Table 2respectively.

The general method of Reaction Scheme 3 through intermediate (12) isdescribed in J. Med. Chem. 1982, 25, 1145. This method is used forpreparation of the precursor compounds (12) in Reaction Scheme 3 belowwhere Y is N, Ar¹ represents an optionally substituted phenyl oroptionally substituted pyridyl ring and Ar² represents an optionallysubstituted phenyl or optionally substituted pyridine ring.

Generally, benzamidine (10) and ethyl(ethoxymethylene)cyanoacetate (11)in DMF was heated under argon to yield the intermediate (12). Thepurification of which may be facilitated by washing with water anddichloromethane. The haloalkylaryl ketone (6) and sodium hydroxide wereadded to the intermediate (12) in DMF, and the mixture was heated underargon to yield the compounds I (Y═N) of Table 2.

A specific example of this preparation is described next.

PREPARATION OF COMPOUND EXAMPLE 18(5-Amino-2-phenyl-furo[2,3-d]pyrimidin-6-yl)-(2,4-dichloro-phenyl)-methanone(Compound I of Reaction Scheme 3 where Y is N. Ar¹ is 2,4-dichloro-Ph-and Ar² is phenyl)

Step 1: Preparation of starting material4-hydroxy-2-phenyl-pyrimidine-5-carbonitrile (12)

To a stirred solution of benzamidine (1.0 g, 8.32 mmol) in anhydrous DMF(20 mL ) was added Ethyl(ethoxymethylene)cyanoacetate (11) (1.41 g, 8.32mmol, 1.0 equiv ) under argon at 0° C. The mixture was stirred at 0° C.for 2 h and increase to 105° C. for 60 h. The reaction mixture was thencooled to ambient temperature. The mixture was extracted with ethylacetate (2×100 mL ). The combined organic extracts were washed withwater (1×50 mL) and brine (1×50 mL), dried (Na₂SO₄), filtered, andevaporated in vacuo. The residue was washed with water (1×60 mL),dichloromethane ( 1×60 mL) then dried in the vacuum oven to obtain thelight yellow solid as product (0.77 g, 47%). ¹H-NMR (CD₃CN) δ8.25 (s, 1H), 8.06 (d, 2H ), 7.70 (t, 1H ), 7.61 (t, 2H). MS LC-MS (MH⁺=198).

Step 2: Preparation of(5-Amino-2-phenyl-furo[2,3-d]pyrimidin-6-yl)-(2,4-dichloro-phenyl)-methanone

To a stirred solution of 4-hydroxy-2-phenyl-pyrimidine-5-carbonitrile(12) (50 mg, 0.25 mmol, from step 1) and2-chloro-1-(2,4-dichlorophenyl)ethanone (85 mg, 0.38mmol, 1.5 equiv) inanhydrous N,N-dimethylformamide (1.0 mL) was added NaOH ( 30.4 mg, 0.76mmol, 3.0 equiv). The dark brown reaction mixture was stirred at 110° C.for 12 h. The reaction was then poured into ethyl acetate (10 mL) andwater (10 mL). Extracted with ethyl acetate (3×10 mL). The organic layerwas dried (Na₂SO₄), filtered, and evaporated in vacuo. The crude productwas purified by pre-HPLC to provide 9.1 mg (9.3%) of the desiredcompound as yellow solid. ¹H-NMR (CD₃CN) δ 9.36 (s, 1H), 8.50 (d, 2H),7.66 (d, 1H), 7.55 (m, 5H); MS LC-MS (MH⁺=384/386).

2-Halo-1-arylketones (6) used in this invention are either commerciallyavailable or may be prepared as shown in the Reaction Scheme 4. Thebromination or chlorination, using standard conditions, of thecorresponding aryl methyl ketone which was prepared either from arylaldehydes or aryl carboxylic acids using conventional organictransformations, gives compound (6). A specific example is describedbelow:

Preparation of 2-chloro-1-[4-(trifluoromethyl)3-pyridinyl]ethanonehydrochloride

Step 1: In a 250 mL round bottom flask was placed 3.0 g of4-trifluoronicotinic acid (15.7 mmol, 1 eq) in 100 mL of THF. To thiswas added 5.3 mL (3.8 g, 37.7 mmol, 2.4 eq) of triethylamine and 9.8 g(18.8 mmol, 1.2 eq) of PyBOP. This was allowed to stir for 10 min atroom temperature where 2.7 g of Meldrum's acid (18.8 mmol, 1.2 eq) wasadded and the reaction allowed stirring at room temperature overnight.(18 h)

At this point, 30 mL of 1 M HCl (aq) was added and the reaction turnedimmediately from orange to purple. This was then heated at for 18 hgradually turning from purple to yellow. The reaction was then basifiedwith saturated NaHCO₃ and extracted with EtOAc (3×200 mL). The combinedorganic layers were dried, filtered, and evaporated. The residue waspurified via BIOTAGE (35% EtOAc/Hex) to provide methyl4-trifluoromethylnicotinate 1.84 g (62%) of the desired product as acolorless oil. TLC R_(f) =0.57 (50% EtOAc:Hex).

Step 2: In a 100 mL flask was placed 1.84 g (9.7 mmol, 1 eq) of methyl4-trifluoromethylnicotinate in 25 mL of 1 M HCl in CH₃COOH. To this wasthen added 1.3 g of NCS (9.7 mmol, 1 eq) and the reaction allowedstirring overnight (18 h). The mixture was then transferred to a 500 mLErlenmeyer flask and to this was added 300 mL of 2 M HCl in Et₂O withstirring. This resulted in a white precipitate which was then filteredto provide 1.2 g (49%) of the desired2-chloro-1-[4trifluoromethyl)-3-pyridinyl]ethanone hydrochloride as awhite solid. ¹H-NMR (DMSO-d₆) δ 9.21 (s, 1H), 9.02 (d, 1H), 7.94 (d,1H), 5.19 (s, 2H).

The aryl amidine compounds (10) were either purchased from commercialsources or prepared from readily available starting material such asaryl nitriles, aryl carboxylic acids and aryl aldehydes by standardorganic transformations such as those described in Bioorganic &Medicinal Chemistry Letters 2002, 12, 1522-1515, J. Medicinal Chemistry1990, 33 (4), 1230-1241.

Variations of the compounds of the invention can be readily preparedusing the processes described above, or by other standard chemicalprocesses known in the art, by employing appropriate starting materialsthat are readily available and/or are already described herein.

The purification of isomers of a compound of this invention, and theseparation of said isomeric mixtures can be accomplished by standardtechniques known in the art.

Generally, a desired salt of a compound of this invention can beprepared in situ during the final isolation and purification of acompound by means well known in the art. For example, a desired salt canbe prepared by separately reacting the purified compound in its freebase or free acid form with a suitable organic or inorganic acid, orsuitable organic or inorganic base, respectively, and isolating the saltthus formed. In the case of basic compounds, for example, the free baseis treated with anhydrous HCl in a suitable solvent such as THF, and thesalt isolated as a hydrochloride salt. In the case of acidic compounds,the salts may be obtained, for example, by treatment of the free acidwith anhydrous ammonia in a suitable solvent such as ether andsubsequent isolation of the ammonium salt. These methods areconventional and would be readily apparent to one skilled in the art.

COMPOSITIONS OF THE COMPOUNDS OF THIS INVENTION

The compounds of this invention can be utilized to achieve the desiredpharmacological effect by administration to a patient in need thereof inan appropriately formulated pharmaceutical composition. A patient, forthe purpose of this invention, is a mammal, including a human, in needof treatment for the particular condition or disease. Therefore, thepresent invention includes pharmaceutical compositions which arecomprised of a pharmaceutically acceptable carrier and apharmaceutically effective amount of a compound, or salt thereof, of thepresent invention. A pharmaceutically acceptable carrier is any carrierwhich is relatively non-toxic and innocuous to a patient atconcentrations consistent with effective activity of the activeingredient so that any side effects ascribable to the carrier do notvitiate the beneficial effects of the active ingredient. Apharmaceutically effective amount of compound is that amount whichproduces a result or exerts an influence on the particular conditionbeing treated. The compounds of the present invention can beadministered with pharmaceutically-acceptable carriers well known in theart using any effective conventional dosage unit forms, includingimmediate, slow and timed release preparations, orally, parenterally,topically, nasally, ophthalmically, otically, sublingually, rectally,vaginally, and the like.

For oral administration, the compounds can be formulated into solid orliquid preparations such as capsules, pills, tablets, troches, lozenges,melts, powders, solutions, suspensions, or emulsions, and may beprepared according to methods known to the art for the manufacture ofpharmaceutical compositions. The solid unit dosage forms can be acapsule which can be of the ordinary hard- or soft-shelled gelatin typecontaining, for example, surfactants, lubricants, and inert fillers suchas lactose, sucrose, calcium phosphate, and corn starch.

In another embodiment, the compounds of this invention may be tabletedwith conventional tablet bases such as lactose, sucrose and cornstarchin combination with binders such as acacia, corn starch or gelatin,disintegrating agents intended to assist the break-up and dissolution ofthe tablet following administration such as potato starch, alginic acid,corn starch, and guar gum, gum tragacanth, acacia, lubricants intendedto improve the flow of tablet granulation and to prevent the adhesion oftablet material to the surfaces of the tablet dies and punches, forexample talc, stearic acid, or magnesium, calcium or zinc stearate,dyes, coloring agents, and flavoring agents such as peppermint, oil ofwintergreen, or cherry flavoring, intended to enhance the aestheticqualities of the tablets and make them more acceptable to the patient.Suitable excipients for use in oral liquid dosage forms includedicalcium phosphate and diluents such as water and alcohols, forexample, ethanol, benzyl alcohol, and polyethylene alcohols, either withor without the addition of a pharmaceutically acceptable surfactant,suspending agent or emulsifying agent. Various other materials may bepresent as coatings or to otherwise modify the physical form of thedosage unit. For instance tablets, pills or capsules may be coated withshellac, sugar or both.

Dispersible powders and granules are suitable for the preparation of anaqueous suspension. They provide the active ingredient in admixture witha dispersing or wetting agent, a suspending agent and one or morepreservatives. Suitable dispersing or wetting agents and suspendingagents are exemplified by those already mentioned above. Additionalexcipients, for example those sweetening, flavoring and coloring agentsdescribed above, may also be present.

The pharmaceutical compositions of this invention may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oilsuch as liquid paraffin or a mixture of vegetable oils. Suitableemulsifying agents may be (1) naturally occurring gums such as gumacacia and gum tragacanth, (2) naturally occurring phosphatides such assoy bean and lecithin, (3) esters or partial esters derived form fattyacids and hexitol anhydrides, for example, sorbitan monooleate, (4)condensation products of said partial esters with ethylene oxide, forexample, polyoxyethylene sorbitan monooleate. The emulsions may alsocontain sweetening and flavoring agents.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil such as, for example, arachis oil, olive oil, sesameoil or coconut oil, or in a mineral oil such as liquid paraffin. Theoily suspensions may contain a thickening agent such as, for example,beeswax, hard paraffin, or cetyl alcohol. The suspensions may alsocontain one or more preservatives, for example, ethyl or n-propylp-hydroxybenzoate; one or more coloring agents; one or more flavoringagents; and one or more sweetening agents such as sucrose or saccharin.

Syrups and elixirs may be formulated with sweetening agents such as, forexample, glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, and preservative, such asmethyl and propyl parabens and flavoring and coloring agents.

The compounds of this invention may also be administered parenterally,that is, subcutaneously, intravenously, intraocularly, intrasynovially,intramuscularly, or interperitoneally, as injectable dosages of thecompound in a physiologically acceptable diluent with a pharmaceuticalcarrier which can be a sterile liquid or mixture of liquids such aswater, saline, aqueous dextrose and related sugar solutions, an alcoholsuch as ethanol, isopropanol, or hexadecyl alcohol, glycols such aspropylene glycol or polyethylene glycol, glycerol ketals such as2,2-dimethyl-1,1-dioxolane-4-methanol, ethers such as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester or, a fatty acidglyceride, or an acetylated fatty acid glyceride, with or without theaddition of a pharmaceutically acceptable surfactant such as a soap or adetergent, suspending agent such as pectin, carbomers, methycellulose,hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifyingagent and other pharmaceutical adjuvants.

Illustrative of oils which can be used in the parenteral formulations ofthis invention are those of petroleum, animal, vegetable, or syntheticorigin, for example, peanut oil, soybean oil, sesame oil, cottonseedoil, corn oil, olive oil, petrolatum and mineral oil. Suitable fattyacids include oleic acid, stearic acid, isostearic acid and myristicacid. Suitable fatty acid esters are, for example, ethyl oleate andisopropyl myristate. Suitable soaps include fatty acid alkali metal,ammonium, and triethanolamine salts and suitable detergents includecationic detergents, for example dimethyl dialkyl ammonium halides,alkyl pyridinium halides, and alkylamine acetates; anionic detergents,for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether,and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents,for example, fatty amine oxides, fatty acid alkanolamides, andpoly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxidecopolymers; and amphoteric detergents, for example,alkyl-beta-aminopropionates, and 2-alkylimidazoline quarternary ammoniumsalts, as well as mixtures.

The parenteral compositions of this invention will typically containfrom about 0.5% to about 25% by weight of the active ingredient insolution. Preservatives and buffers may also be used advantageously. Inorder to minimize or eliminate irritation at the site of injection, suchcompositions may contain a non-ionic surfactant having ahydrophile-lipophile balance (HLB) of from about 12 to about 17. Thequantity of surfactant in such formulation ranges from about 5% to about15% by weight. The surfactant can be a single component having the aboveHLB or can be a mixture of two or more components having the desiredHLB.

Illustrative of surfactants used in parenteral formulations are theclass of polyethylene sorbitan fatty acid esters, for example, sorbitanmonooleate and the high molecular weight adducts of ethylene oxide witha hydrophobic base, formed by the condensation of propylene oxide withpropylene glycol.

The pharmaceutical compositions may be in the form of sterile injectableaqueous suspensions. Such suspensions may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents such as, for example, sodium carboxymethylcellulose,methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate,polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing orwetting agents which may be a naturally occurring phosphatide such aslecithin, a condensation product of an alkylene oxide with a fatty acid,for example, polyoxyethylene stearate, a condensation product ofethylene oxide with a long chain aliphatic alcohol, for example,heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxidewith a partial ester derived form a fatty acid and a hexitol such aspolyoxyethylene sorbitol monooleate, or a condensation product of anethylene oxide with a partial ester derived from a fatty acid and ahexitol anhydride, for example polyoxyethylene sorbitan monooleate.

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent. Diluents and solvents that may be employed are, for example,water, Ringer's solution, isotonic sodium chloride solutions andisotonic glucose solutions. In addition, sterile fixed oils areconventionally employed as solvents or suspending media. For thispurpose, any bland, fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid can be usedin the preparation of injectables.

A composition of the invention may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritationexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such material are, for example, cocoa butter and polyethyleneglycol.

Another formulation employed in the methods of the present inventionemploys transdermal delivery devices (“patches”). Such transdermalpatches may be used to provide continuous or discontinuous infusion ofthe compounds of the present invention in controlled amounts. Theconstruction and use of transdermal patches for the delivery ofpharmaceutical agents is well known in the art (see, e.g., U.S. Pat. No.5,023,252, issued Jun. 11, 1991, incorporated herein by reference). Suchpatches may be constructed for continuous, pulsatile, or on demanddelivery of pharmaceutical agents.

Controlled release formulations for parenteral administration includeliposomal, polymeric microsphere and polymeric gel formulations whichare known in the art.

It may be desirable or necessary to introduce the pharmaceuticalcomposition to the patient via a mechanical delivery device. Theconstruction and use of mechanical delivery devices for the delivery ofpharmaceutical agents is well known in the art. Direct techniques for,for example, administering a drug directly to the brain usually involveplacement of a drug delivery catheter into the patient's ventricularsystem to bypass the blood-brain barrier. One such implantable deliverysystem, used for the transport of agents to specific anatomical regionsof the body, is described in U.S. Pat. No. 5,011,472, issued Apr. 30,1991.

The compositions of the invention can also contain other conventionalpharmaceutically acceptable compounding ingredients, generally referredto as carriers or diluents, as necessary or desired. Conventionalprocedures for preparing such compositions in appropriate dosage formscan be utilized. Such ingredients and procedures include those describedin the following references, each of which is incorporated herein byreference: Powell, M. F. et al, “Compendium of Excipients for ParenteralFormulations” PDA Journal of Pharmaceutical Science & Technology 1998,52(5), 238-311; Strickley, R. G “Parenteral Formulations of SmallMolecule Therapeutics Marketed in the United States (1999)-Part-1” PDAJournal of Pharmaceutical Science & Technology 1999, 53(6), 324-349; andNema, S. et al, “Excipients and Their Use in Injectable Products” PDAJournal of Pharmaceutical Science & Technology 1997, 51(4), 166-171.

Commonly used pharmaceutical ingredients which can be used asappropriate to formulate the composition for its intended route ofadministration include:

acidifying agents (examples include but are not limited to acetic acid,citric acid, fumaric acid, hydrochloric acid, nitric acid);

alkalinizing agents (examples include but are not limited to ammoniasolution, ammonium carbonate, diethanolamine, monoethanolamine,potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide,triethanolamine, trolamine);

adsorbents (examples include but are not limited to powdered celluloseand activated charcoal);

aerosol propellants (examples include but are not limited to carbondioxide, CCl₂F₂, F₂ClC—CClF₂ and CClF₃)

air displacement agents (examples include but are not limited tonitrogen and argon);

antifungal preservatives (examples include but are not limited tobenzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben,sodium benzoate);

antimicrobial preservatives (examples-include but are not limited tobenzalkonium chloride, benzethonium chloride, benzyl alcohol,cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol,phenylmercuric nitrate and thimerosal);

antioxidants (examples include but are not limited to ascorbic acid,ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene,hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate,sodium bisulfite, sodium formaldehyde sulfoxylate, sodiummetabisulfite);

binding materials (examples include but are not limited to blockpolymers, natural and synthetic rubber, polyacrylates, polyurethanes,silicones, polysiloxanes and styrene-butadiene copolymers);

buffering agents (examples include but are not limited to potassiummetaphosphate, dipotassium phosphate, sodium acetate, sodium citrateanhydrous and sodium citrate dihydrate)

carrying agents (examples include but are not limited to acacia syrup,aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orangesyrup, syrup, corn oil, mineral oil, peanut oil, sesame oil,bacteriostatic sodium chloride injection and bacteriostatic water forinjection)

chelating agents (examples include but are not limited to edetatedisodium and edetic acid)

colorants (examples include but are not limited to FD&C Red No. 3, FD&CRed No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&COrange No. 5, D&C Red No. 8, caramel and ferric oxide red);

clarifying agents (examples include but are not limited to bentonite);

emulsifying agents (examples include but are not limited to acacia,cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitanmonooleate, polyoxyethylene 50 monostearate);

encapsulating agents (examples include but are not limited to gelatinand cellulose acetate phthalate)

flavorants (examples include but are not limited to anise oil, cinnamonoil, cocoa, menthol, orange oil, peppermint oil and vanillin);

humectants (examples include but are not limited to glycerol, propyleneglycol and sorbitol);

levigating agents (examples include but are not limited to mineral oiland glycerin);

oils (examples include but are not limited to arachis oil, mineral oil,olive oil, peanut oil, sesame oil and vegetable oil);

ointment bases (examples include but are not limited to lanolin,hydrophilic ointment, polyethylene glycol ointment, petrolatum,hydrophilic petrolatum, white ointment, yellow ointment, and rose waterointment);

penetration enhancers (transdermal delivery) (examples include but arenot limited to monohydroxy or polyhydroxy alcohols, mono-or polyvalentalcohols, saturated or unsaturated fatty alcohols, saturated orunsaturated fatty esters, saturated or unsaturated dicarboxylic acids,essential oils, phosphatidyl derivatives, cephalin, terpenes, amides,ethers, ketones and ureas)

plasticizers (examples include but are not limited to diethyl phthalateand glycerol);

solvents (examples include but are not limited to ethanol, corn oil,cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanutoil, purified water, water for injection, sterile water for injectionand sterile water for irrigation);

stiffening agents (examples include but are not limited to cetylalcohol, cetyl esters wax, microcrystalline wax, paraffin, stearylalcohol, white wax and yellow wax);

suppository bases (examples include but are not limited to cocoa butterand polyethylene glycols (mixtures));

surfactants (examples include but are not limited to benzalkoniumchloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium laurylsulfate and sorbitan mono-palmitate);

suspending agents (examples include but are not limited to agar,bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,kaolin, methylcellulose, tragacanth and veegum);

sweetening agents (examples include but are not limited to aspartame,dextrose, glycerol, mannitol, propylene glycol, saccharin sodium,sorbitol and sucrose);

tablet anti-adherents (examples include but are not limited to magnesiumstearate and talc);

tablet binders (examples include but are not limited to acacia, alginicacid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose,gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinylpyrrolidone, and pregelatinized starch);

tablet and capsule diluents (examples include but are not limited todibasic calcium phosphate, kaolin, lactose, mannitol, microcrystallinecellulose, powdered cellulose, precipitated calcium carbonate, sodiumcarbonate, sodium phosphate, sorbitol and starch);

tablet coating agents (examples include but are not limited to liquidglucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, cellulose acetatephthalate and shellac);

tablet direct compression excipients (examples include but are notlimited to dibasic calcium phosphate);

tablet disintegrants (examples include but are not limited to alginicacid, carboxymethylcellulose calcium, microcrystalline cellulose,polacrillin potassium, cross-linked polyvinylpyrrolidone, sodiumalginate, sodium starch glycollate and starch);

tablet glidants (examples include but are not limited to colloidalsilica, corn starch and talc);

tablet lubricants (examples include but are not limited to calciumstearate, magnesium stearate, mineral oil, stearic acid and zincstearate);

tablet/capsule opaquants (examples include but are not limited totitanium dioxide);

tablet polishing agents (examples include but are not limited to camubawax and white wax);

thickening agents (examples include but are not limited to beeswax,cetyl alcohol and paraffin);

tonicity agents (examples include but are not limited to dextrose andsodium chloride);

viscosity increasing agents (examples include but are not limited toalginic acid, bentonite, carbomers, carboxymethylcellulose sodium,methylcellulose, polyvinyl pyrrolidone, sodium alginate and tragacanth);and

wetting agents (examples include but are not limited toheptadecaethylene oxycetanol, lecithins, sorbitol monooleate,polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).

It is believed that one skilled in the art, utilizing the precedinginformation, can utilize the present invention to its fullest extent.Nevertheless, the following are examples of pharmaceutical formulationsthat can be used in the method of the present invention. They are forillustrative purposes only, and are not to be construed as limiting theinvention in any way.

Useful pharmaceutical compositions for administration of the compoundsaccording to the present invention can be illustrated as follows:

Sterile IV Solution: A 5 mg/mL solution of the desired compound of thisinvention is made using sterile, injectable water, and the pH isadjusted if necessary. The solution is diluted for administration to 1-2mg/mL with sterile 5% dextrose and is administered as an IV infusionover 60 minutes.

Lyophilized powder for IV administration: A sterile preparation can beprepared with (i) 100-1000 mg of the desired compound of this inventionas a lypholized powder, (ii) 32-327 mg/mL sodium citrate, and (iii)300-3000 mg Dextran 40. The formulation is reconstituted with sterile,injectable saline or dextrose 5% to a concentration of 10 to 20 mg/mL,which is further diluted with saline or dextrose 5% to 0.2-0.4 mg/mL,and is administered either IV bolus or by IV infusion over 15-60minutes.

Intramuscular suspension: The following solution or suspension can beprepared, for intramuscular injection:

-   -   50 mg/mL of the desired, water-insoluble compound of this        invention    -   5 mg/mL sodium carboxymethylcellulose    -   4 mg/mL TWEEN 80    -   9 mg/mL sodium chloride    -   9 mg/mL benzyl alcohol

Hard Shell Capsules: A large number of unit capsules are prepared byfilling standard two-piece hard galantine capsules each with 100 mg ofpowdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6mg of magnesium stearate.

Soft Gelatin Capsules: A mixture of active ingredient in a digestibleoil such as soybean oil, cottonseed oil or olive oil is prepared andinjected by means of a positive displacement pump into molten gelatin toform soft gelatin capsules containing 100 mg of the active ingredient.The capsules are washed and dried. The active ingredient can bedissolved in a mixture of polyethylene glycol, glycerin and sorbitol toprepare a water miscible medicine mix.

Tablets: A large number of tablets are prepared by conventionalprocedures so that the dosage unit was 100 mg of active ingredient, 0.2mg. of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg ofmicrocrystalline cellulose, 11 mg. of starch, and 98.8 mg of lactose.Appropriate aqueous and non-aqueous coatings may be applied to increasepalatability, improve elegance and stability or delay absorption.

Immediate Release Tablets/Capsules: These are solid oral dosage formsmade by conventional and novel processes. These units are taken orallywithout water for immediate dissolution and delivery of the medication.The active ingredient is mixed in a liquid containing ingredient such assugar, gelatin, pectin and sweeteners. These liquids are solidified intosolid tablets or caplets by freeze drying and solid state extractiontechniques. The drug compounds may be compressed with viscoelastic andthermoelastic sugars and polymers or effervescent components to produceporous matrices intended for immediate release, without the need ofwater.

Method of Treating Hyper-Proliferative Disorders

The present invention relates to a method for using the compoundsdescribed above, including salts thereof and compositions thereof, totreat mammalian hyper-proliferative disorders. This method comprisesadministering to a mammal in need thereof, including a human, an amountof a compound of this invention, or a pharmaceutically acceptable saltthereof, which is effective to treat the disorder. Hyper-proliferativedisorders include but are not limited to solid tumors, such as cancersof the breast, respiratory tract, brain, reproductive organs, digestivetract, urinary tract, eye, liver, skin, head and neck, thyroid,parathyroid and their distant metastases. Those disorders also includelymphomas, sarcomas, and leukemias.

Examples of breast cancer include, but are not limited to invasiveductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ,and lobular carcinoma in situ.

Examples of cancers of the respiratory tract include, but are notlimited to small-cell and non-small-cell lung carcinoma, as well asbronchial adenoma and pleuropulmonary blastoma.

Examples of brain cancers include, but are not limited to brain stem andhypophtalmic glioma, cerebellar and cerebral astrocytoma,medulloblastoma, ependymoma, as well as neuroectodermal and pinealtumor.

Tumors of the male reproductive organs include, but are not limited toprostate and testicular cancer. Tumors of the female reproductive organsinclude, but are not limited to endometrial, cervical, ovarian, vaginal,and vulvar cancer, as well as sarcoma of the uterus.

Tumors of the digestive tract include, but are not limited to anal,colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal,small-intestine, and salivary gland cancers.

Tumors of the urinary tract include, but are not limited to bladder,penile, kidney, renal pelvis, ureter, and urethral cancers.

Eye cancers include, but are not limited to intraocular melanoma andretinoblastoma.

Examples of liver cancers include, but are not limited to hepatocellularcarcinoma (liver cell carcinomas with or without fibrolamellar variant),cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixedhepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to squamous cell carcinoma,Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, andnon-melanoma skin cancer.

Head-and-neck cancers include, but are not limited tolaryngeal/hypopharyngeal/nasopharyngeal/oropharyngeal cancer, and lipand oral cavity cancer.

Lymphomas include, but are not limited to AIDS-related lymphoma,non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Hodgkin's disease,and lymphoma of the central nervous system.

Sarcomas include, but are not limited to sarcoma of the soft tissue,osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, andrhabdomyosarcoma.

Leukemias include, but are not limited to acute myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, chronicmyelogenous leukemia, and hairy cell leukemia.

These disorders have been well characterized in humans, but also existwith a similar etiology in other mammals, and can be treated byadministering pharmaceutical compositions of the present invention.

The utility of the compounds of the present invention can beillustrated, for example, by their activity in vitro in the in vitrotumor cell proliferation assay described below. The link betweenactivity in tumor cell proliferation assays in vitro and anti-tumoractivity in the clinical setting has been very well established in theart. For example, the therapeutic utility of taxol (Silvestrini et al.Stem Cells 1993, 11(6), 528-35), taxotere (Bissery et al. Anti CancerDrugs 1995, 6(3), 339), and topoisomerase inhibitors (Edelman et al.Cancer Chemother. Pharmacol. 1996, 37(5), 385-93) was demonstrated withthe use of in vitro tumor proliferation assays.

The following assay is one of the methods by which compound activityrelating to treatment of the disorders identified herein can bedetermined.

In Vitro Tumor Cell Proliferation Assay

The adherent tumor cell proliferation assay used to test the compoundsof the present invention involves a readout called Cell Titre-Glodeveloped by Promega (Cunningham, B A “A Growing Issue: CellProliferation Assays. Modem kits ease quantification of cell growth” TheScientist 2001, 15(13), 26, and Crouch, S P et al., “The use of ATPbioluminescence as a measure of cell proliferation and cytotoxicity”Journal of Immunological Methods 1993, 160, 81-88).

H460 cells (lung carcinoma, purchased from ATCC) are plated in 96-wellplates at 3000 cells/well in complete media with 10% Fetal Calf Serumand incubated 24 hours at 37° C. 24 hrs after plating, test compoundsare added over a final concentration range of 10 nM to 20 M in serialdilutions a t a final DMSO concentration of 0.2%. Cells are incubatedfor 72 hours at 37° C. in complete growth media after compound addition.Using the Promega Cell Titer Glo Luminescent assay kit, the number ofviable cells/well is determined via measurement of luminescent signalbased on amount of intracellular ATP content in cells. Values read at24-hour incubation are subtracted as Day 0. For determination of IC50's,a linear regression analysis can be used to determine drug concentrationwhich results in a 50% inhibition of cell proliferation using this assayformat. Representative compounds of the present invention showed asignificant inhibition of tumor cell proliferation in this assay.

Based upon the above and other standard laboratory techniques known toevaluate compounds useful for the treatment of hyper-proliferativedisorders, by standard toxicity tests and by standard pharmacologicalassays for the determination of treatment of the conditions identifiedabove in mammals, and by comparison of these results with the results ofknown medicaments that are used to treat these conditions, the effectivedosage of the compounds of this invention can readily be determined fortreatment of each desired indication. The amount of the activeingredient to be administered in the treatment of one of theseconditions can vary widely according to such considerations as theparticular compound and dosage unit employed, the mode ofadministration, the period of treatment, the age and sex of the patienttreated, and the nature and extent of the condition treated.

The total amount of the active ingredient to be administered willgenerally range from about 0.001 mg/kg to about 200 mg/kg, andpreferably from about 0.01 mg/kg to about 20 mg/kg body weight per day.A unit dosage may contain from about 0.5 mg to about 1500 mg of activeingredient, and can be administered one or more times per day. The dailydosage for administration by injection, including intravenous,intramuscular, subcutaneous and parenteral injections, and use ofinfusion techniques will preferably be from 0.01 to 200 mg/kg of totalbody weight. The daily rectal dosage regimen will preferably be from0.01 to 200 mg/kg of total body weight. The daily vaginal dosage regimenwill preferably be from 0.01 to 200 mg/kg of total body weight. Thedaily topical dosage regimen will preferably be from 0.1 to 200 mgadministered between one to four times daily. The transdermalconcentration will preferably be that required to maintain a daily doseof from 0.01 to 200 mg/kg. The daily inhalation dosage regimen willpreferably be from 0.01 to 100 mg/kg of total body weight.

Of course the specific initial and continuing dosage regimen for eachpatient will vary according to the nature and severity of the conditionas determined by the attending diagnostician, the activity of thespecific compound employed, the age and general condition of thepatient, time of administration, route of administration, rate ofexcretion of the drug, drug combinations, and the like. The desired modeof treatment and number of doses of a compound of the present inventionor a pharmaceutically acceptable salt or ester or composition thereofcan be ascertained by those skilled in the art using conventionaltreatment tests.

The compounds or compositions of this invention can be administered asthe sole pharmaceutical agent or in combination with one or more otherpharmaceutical agents where the combination causes no unacceptableadverse effects. For example, the compounds of this invention can becombined with known anti-hyper-proliferative or other indication agents,and the like, as well as with admixtures and combinations thereof.

Optional anti-hyper-proliferative agents which can be added to oradministered in conjunction with a compound or composition of thisinvention include but are not limited to compounds listed on the cancerchemotherapy drug regimens in the 11^(th) Edition of the Merck Index,(1996), which is hereby incorporated by reference. These compoundsinclude asparaginase, bleomycin, carboplatin, carmustine, chlorambucil,cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine,dactinomycin, daunorubicin, doxorubicin(adriamycine), epirubicin,etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide,irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine,mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone,prednisone, procarbazine, raloxifen, streptozocin, tamoxifen,thioguanine, topotecan, vinblastine, vincristine, and vindesine.

Other ant-hyper-proliferative agents suitable for use with thisinvention include but are not limited to those compounds acknowledged tobe used in the treatment of neoplastic diseases in Goodman and Gilman'sThe Pharmacological Basis of Therapeutics (Ninth Edition), editorMolinoff et al., publ. by McGraw-Hill, pages 1225-1287, (1996), which ishereby incorporated by reference, such as aminoglutethimide,L-asparaginase, azathioprine, 5-azacytidine cladribine, busulfan,diethylstilbestrol, 2′, 2′-difluorodeoxycytidine, docetaxel,erythrohydroxynonyladenine, ethinyl estradiol, 5-fluorodeoxyuridine,5-fluorodeoxyuridine monophosphate, fludarabine phosphate,fluoxymesterone, flutamide, hydroxyprogesterone caproate, idarubicin,interferon, medroxyprogesterone acetate, megestrol acetate, melphalan,mitotane, paclitaxel, pentostatin, N-phosphonoacetyl-L-aspartate (PALA),plicamycin, semustine, teniposide, testosterone propionate, thiotepa,trimethylmelamine, uridine, and vinorelbine. Otheranti-hyper-proliferative agents suitable for use with this inventioninclude but are not limited to other anti-cancer agents such asepothilone, irinotecan, raloxifen and topotecan.

It is believed that one skilled in the art, utilizing the precedinginformation, can utilize the present invention to its fullest extent.

It should be apparent to one of ordinary skill in the art that changesand modifications can be made to this invention without departing fromthe spirit or scope of the invention as it is set forth herein.

1. A compound of Formula I

wherein Y is CH or N; Ar¹ is phenyl or pyridyl each optionallysubstituted with 1 or 2 substituents each selected independently from(C₁-C₃)alkoxy, halo, OH, CF₃, CN, NO₂and (C₁-C₃)alkyl, said alkyl beingoptionally substituted with CF₃; Ar² is phenyl or pyridyl eachoptionally substituted with 1 or 2 substituents each independentlyselected from halo, OH, CN, NO₂, CF₃, (C₁-C₆)alkoxy, NR¹R¹, S(O)₂R²,C(O)R³, and (C₁-C₆)alkyl optionally substituted with R⁴; R¹ is selectedfrom H, S(O)₂N[(C₁-C₃)alkyl]₂, S(O)₂NH(C₁-C₃)alkyl, C(O)(C₁-C₃)alkylwhere said alkyl is optionally substituted with NR⁵R⁵, and (C₁-C₃)alkylwhere said alkyl is optionally substituted with 1 or 2 substituents eachselected independently from OH and (C₁-C₃)alkoxy, with the proviso thatin any NR¹R¹ group when one R¹ is S(O)₂N[(C₁-C₃)alkyl]₂,S(O)₂NH(C₁-C₃)alkyl or C(O)(C₁-C₃)alkyl then the other R¹ must be otherthan S(O)₂N[(C₁-C₃)alkyl]₂, S(O)₂NH(C₁-C₃)alkyl or C(O)(C₁-C₃)alkyl; R²is selected from (C₁-C₃)alkyl, pyrrolidinyl, and NH(C₁-C₃)alkyl wheresaid alkyl is optionally substituted with OH; R³ is selected from(C₁-C₃)alkyl, (C₁-C₃)alkoxy, morpholinyl, pyrrolidinyl, piperidinyl, andNH(C₁-C₃)alkyl where said alkyl is optionally substituted with OH,(C₁-C₃)alkoxy or N[(C₁-C₃)alkyl]₂; R⁴is selected from OH, CN, CF₃,(C₁-C₃)alkoxy, C(O)NR⁵R⁵, NR⁵R⁵, and piperidinyl; and R⁵ is selectedfrom H, (C₁-C₃)alkyl, C(O)(C₁-C₃)alkyl, S(O)₂(C₁-C₃)alkyl andpiperidinyl, with the proviso that in any NR⁵R⁵ group when one R⁵ isC(O)(C₁-C₃)alkyl or S(O)₂(C₁-C₃)alkyl, then the other R⁵ must be otherthan C(O)(C₁-C₃)alkyl or S(O)₂(C₁-C₃)alkyl; and excluding(3-amino-6-phenylfuro[2,3-b]pyridin-2-yl)(phenyl)methanone,(3-amino-6-phenylfuro[2,3-b]pyridin-2-yl)(4-nitrophenyl)methanone, and(3-amino-6-(4-methylphenyl)furo[2,3-b]pyridin-2-yl)(phenyl)methanone, ora pharmaceutically acceptable salt thereof.
 2. A compound of claim 1wherein Y is CH.
 3. A compound of claim 2 wherein Ar¹ is optionallysubstituted phenyl.
 4. A compound of claim 2 wherein Ar¹ is optionallysubstituted pyridyl.
 5. A compound of claim 2 wherein Ar² is optionallysubstituted phenyl.
 6. A compound of claim 2 wherein Ar² is optionallysubstituted pyridyl.
 7. A compound of claim 3 wherein Ar² is optionallysubstituted pyridyl.
 8. A compound of claim 3 wherein Ar² is optionallysubstituted phenyl.
 9. A compound of claim 4 wherein Ar² is optionallysubstituted phenyl.
 10. A compound of claim 4 wherein Ar² is optionallysubstituted pyridyl.
 11. A compound of claim 1 wherein Y is N.
 12. Acompound of claim 11 wherein Ar¹ is optionally substituted phenyl.
 13. Acompound of claim 11 wherein Ar¹ is optionally substituted pyridyl. 14.A compound of claim 11 wherein Ar² is optionally substituted phenyl. 15.A compound of claim 11 wherein Ar² is optionally substituted pyridyl.16. A compound of claim 12 wherein Ar² is optionally substitutedpyridyl.
 17. A compound of claim 12 wherein Ar² is optionallysubstituted phenyl.
 18. A compound of claim 13 wherein Ar² is optionallysubstituted phenyl.
 19. A compound of claim 13 wherein Ar² is optionallysubstituted pyridyl.
 20. A compound of claim 11 wherein Ar¹ and Ar² areeach substituted phenyl.
 21. A compound of claim 11 wherein Ar¹ isphenyl substituted with at least 1 substituent selected from(C₁-C₃)alkoxy, halo, OH, CF₃, CN, or (C₁-C₃)alkyl, said alkyl beingoptionally substituted with CF₃;
 22. A compound of claim 11 wherein Ar²is substituted with at least 1 substituent selected from halo, OH, CN,NO₂, CF₃, (C₁-C₆)alkoxy, NR¹R¹, S(O)₂R², C(O)R³, and (C_(1-C) ₆)alkylsubstituted with R⁴;
 23. A pharmaceutical composition comprising acompound of Formula I

wherein Y is CH or N; Ar¹ is phenyl or pyridyl each optionallysubstituted with 1 or 2 substituents each selected independently from(C₁-C₃)alkoxy, halo, OH, CF₃, CN, NO₂and (C₁-C₃)alkyl, said alkyl beingoptionally substituted with CF₃; Ar² is phenyl or pyridyl eachoptionally substituted with 1 or 2 substituents each independentlyselected from halo, OH, CN, NO₂, CF₃, (C₁-C₆)alkoxy, NR¹R¹, S(O)₂R²,C(O)R³, and (C₁-C₆)alkyl optionally substituted with R⁴; R¹ is selectedfrom H, S(O)₂N[(C₁-C₃)alkyl]₂, S(O)₂NH(C₁-C₃)alkyl, C(O)(C₁-C₃)alkylwhere said alkyl is optionally substituted with NR⁵R⁵, and (C₁-C₃)alkylwhere said alkyl is optionally substituted with 1 or 2 substituents eachselected independently from OH and (C₁-C₃)alkoxy, with the proviso thatin any NR¹R¹ group when one R¹ is S(O)₂N[(C₁-C₃)alkyl]₂,S(O)₂NH(C₁-C₃)alkyl or C(O)(C₁-C₃)alkyl then the other R¹ must be otherthan S(O)₂N[(C₁-C₃)alkyl]₂, S(O)₂NH(C₁-C₃)alkyl or C(O)(C₁-C₃)alkyl; R²is selected from (C₁-C₃)alkyl, pyrrolidinyl, and NH(C₁-C₃)alkyl wheresaid alkyl is optionally substituted with OH; R³ is selected from(C₁-C₃)alkyl, (C₁-C₃)alkoxy, morpholinyl, pyrrolidinyl, piperidinyl, andNH(C₁-C₃)alkyl where said alkyl is optionally substituted with OH,(C₁-C₃)alkoxy or N[(C₁-C₃)alkyl]₂; R⁴ is selected from OH, CN, CF₃,(C₁-C₃)alkoxy, C(O)NR⁵R⁵, NR⁵R⁵, and piperidinyl; and R⁵ is selectedfrom H, (C₁-C₃)alkyl, C(O)(C₁-C₃)alkyl, S(O)₂(C₁-C₃)alkyl andpiperidinyl, with the proviso that in any NR⁵R⁵ group when one R⁵ isC(O)(C₁-C₃)alkyl or S(O)₂(C₁-C₃)alkyl, then the other R⁵ must be otherthan C(O)(C₁-C₃)alkyl or S(O)₂(C₁-C₃)alkyl; and excluding(3-amino-6-phenylfuro[2,3-b]pyridin-2-yl)(phenyl)methanone,(3-amino-6-phenylfuro[2,3-b]pyridin-2-yl)(4-nitrophenyl)methanone, and(3-amino-6-(4-methylphenyl)furo[2,3-b]pyridin-2-yl)(phenyl)methanone, ora pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 24. A method of treating a hyper-proliferativedisorder comprising the administration to a patient in need thereof ofan effective amount of a compound of Formula

wherein Y is CH or N; Ar¹ is phenyl or pyridyl each optionallysubstituted with 1 or 2 substituents each selected independently from(C₁-C₃)alkoxy, halo, OH, CF₃, CN, NO₂ and (C₁-C₃)alkyl, said alkyl beingoptionally substituted with CF₃; Ar² is phenyl or pyridyl eachoptionally substituted with 1 or 2 substituents each independentlyselected from halo, OH, CN, NO₂, CF₃, (C₁-C₆)alkoxy, NR¹R¹, S(O)₂R²,C(O)R³, and (C₁-C₆)alkyl optionally substituted with R⁴; R¹ is selectedfrom H, S(O)₂N[(C₁-C₃)alkyl]₂, S(O)₂NH(C₁-C₃)alkyl, C(O)(C₁-C₃)alkylwhere said alkyl is optionally substituted with NR⁵R⁵, and (C₁-C₃)alkylwhere said alkyl is optionally substituted with 1 or 2 substituents eachselected independently from OH and (C₁-C₃)alkoxy, with the proviso thatin any NR¹R¹ group when one R¹ is S(O)₂N[(C₁-C₃)alkyl]₂,S(O)₂NH(C₁-C₃)alkyl or C(O)(C₁-C₃)alkyl then the other R¹ must be otherthan S(O)₂N[(C₁-C₃)alkyl]₂, S(O)₂NH(C₁-C₃)alkyl or C(O)(C₁-C₃)alkyl; R²is selected from (C₁-C₃)alkyl, pyrrolidinyl, and NH(C₁-C₃)alkyl wheresaid alkyl is optionally substituted with OH; R³ is selected from(C₁-C₃)alkyl, (C₁-C₃)alkoxy, morpholinyl, pyrrolidinyl, piperidinyl, andNH(C₁-C₃)alkyl where said alkyl is optionally substituted with OH,(C₁-C₃)alkoxy or N[(C₁-C₃)alkyl]₂; R⁴ is selected from OH, CN, CF₃,(C₁-C₃)alkoxy, C(O)NR⁵R⁵, NR⁵R⁵, and piperidinyl; and R⁵ is selectedfrom H, (C₁-C₃)alkyl, C(O)(C₁-C₃)alkyl, S(O)₂(C₁-C₃)alkyl andpiperidinyl, with the proviso that in any NR⁵R⁵ group when one R⁵ isC(O)(C₁-C₃)alkyl or S(O)₂(C₁-C₃)alkyl, then the other R⁵ must be otherthan C(O)(C₁-C₃)alkyl or S(O)₂(C₁-C₃)alkyl; and excluding(3-amino-6-phenylfuro[2,3-b]pyridin-2-yl)(phenyl)methanone,(3-amino-6-phenylfuro[2,3b]pyridin-2-yl)(4-nitrophenyl)methanone, and(3-amino-6-(4-methylphenyl)furo[2,3-b]pyridin-2-yl)(phenyl)methanone, ora pharmaceutically acceptable salt thereof.